Chronic myelocytic leukemia (CIVIL) is a malignant neoplasm affecting the blood and bone marrow which may occur at all ages, and most patients are middle-aged or elderly people, and male patients are slightly more than female patients. In western populations, CIVIL patients account for 15%-20% of adult leukemia patients. According to the characters and research of clinical significance, CIVIL is usually divided into three categories. With the absence of intervention factors, CML usually starts from the “chronic phase”, and after several years CML enters the “acceleration phase”, and ultimately it goes into the “blast phase”. Blast phase is the final phase of CML with a pathological condition similar to acute leukemia. If drug treatment is taken in time, this progressive process is usually stopped.
In the chronic phase of CML, imatinib (with a trade name of “Gleevec”) is the preferred tyrosine kinase inhibitor. This drug was approved by the U.S. Food and Drug Administration (FDA) in 2001 and has been demonstrated to inhibit bone hyperplasia diseases (cytogenetic response) in vivo of majority of CML patients (65-75%). However, the mutation of BCR-ABL kinase domain in many tumor cells results in the imatinib resistance in many patients. Hence, a number of new products get promoted. One of them is called dasatinib (with a trade name of “Sprycel”), which can block multiple oncogenic proteins, and was approved by FDA to be applied for patients in all disease phases of CIVIL with previous treatment failure or intolerance, and also for the adult ALL patients who are Philadelphia chromosome-positive with resistant or intolerance to other therapies. The structure of dasatinib is shown as formula (XII):

Clinical trials show that the curative effect of dasatinib is better than that of imatinib with high dose, and no resistance of dasatinib is found, but in the process of application, there are still some adverse drug reactions, such as fever, pleural effusion, febrile neutropenia, gastrointestinal bleeding, pneumonia, thrombocytopenia, dyspnea, anemia, diarrhea and cardiac failure etc. In addition, FDA announced that dasatinib might increase the risk of pulmonary hypertension in October 2011, therefore, FDA decided to add this risk information into warnings and precautions in the drug instructions of Sprycel. Therefore, certain modifications of dasatinib and its derivatives may help to increase curative effect thereof and reduce possible toxic and side effects.
Polyethylene glycol (PEG) modification technology is a new drug administration technology which has developed rapidly in recent years and is mainly applied in the injection administration system. It is a technology linking activated polyethylene glycol to a drug molecule or its surface. Small molecule drugs, after being modified by polyethylene glycol, mainly have the following advantages: 1. increased water-solubility of drugs; 2. reduced toxicity; 3. prolonged cyclic half-life of drugs, reduced times of administration, improved patient compliance, improved life quality and reduced treatment fees; 4. reduced enzyme degradation and improved bioavailability; 5. decreased permeability of blood-brain barrier and reduced central side effects. After the drugs being linked with polyethylene glycol, pharmacokinetics of the drugs changes and thereby pharmacodynamics thereof changes. Especially polyethylene glycol could prolong the time for plasma concentration being maintained or close to the target concentration to make the drug efficacy to be fully realized. Additionally, the drugs linked with polyethylene glycol have a water-solubility which is greatly improved, and more importantly could achieve a purposes of “passive targeting” administration. The mechanism of passive targeting is determined by effective penetration of macromolecular prodrugs into the tumor tissues, and the penetration ability is closely associated with the molecule size and structure type of polyethylene glycol and other factors.
In the invention WO2010120387 disclosed, the modification of tyrosine kinase inhibitor class (Tinibs) of antitumor drugs by polyethylene glycol is adopted, but the molecule size and structure type of polyethylene glycol and other factors are not fully considered, and the polyethylene glycol molecules chosen in this invention are single-functional or double-functional linear configuration molecules. The obvious drawbacks of the modification of small molecule drugs by this kind of linear configuration polyethylene glycol are a small drug loading, a large proportion of inactive molecules, and problems in metabolism, clear of drugs and so on.